title: CaBP1 regulates voltage-dependent inactivation and activation of Ca(V)1.2 (L-type) calcium channels.
abstract: CaBP1 is a Ca(2+)-binding protein that regulates the gating of voltage-gated (Ca(V)) Ca(2+) channels. In the Ca(V)1.2 channel α(1)-subunit (α(1C)), CaBP1 interacts with cytosolic N- and C-terminal domains and blunts Ca(2+)-dependent inactivation. To clarify the role of the α(1C) N-terminal domain in CaBP1 regulation, we compared the effects of CaBP1 on two alternatively spliced variants of α(1C) containing a long or short N-terminal domain. In both isoforms, CaBP1 inhibited Ca(2+)-dependent inactivation but also caused a depolarizing shift in voltage-dependent activation and enhanced voltage-dependent inactivation (VDI). In binding assays, CaBP1 interacted with the distal third of the N-terminal domain in a Ca(2+)-independent manner. This segment is distinct from the previously identified calmodulin-binding site in the N terminus. However, deletion of a segment in the proximal N-terminal domain of both α(1C) isoforms, which spared the CaBP1-binding site, inhibited the effect of CaBP1 on VDI. This result suggests a modular organization of the α(1C) N-terminal domain, with separate determinants for CaBP1 binding and transduction of the effect on VDI. Our findings expand the diversity and mechanisms of Ca(V) channel regulation by CaBP1 and define a novel modulatory function for the initial segment of the N terminus of α(1C).
authors.affiliation: Department of Physiology and Pharmacology, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Shimrit
authors.initials: S
authors.lastname: Oz
authors.forename: Vladimir
authors.initials: V
authors.lastname: Tsemakhovich
authors.forename: Carl J
authors.initials: CJ
authors.lastname: Christel
authors.forename: Amy
authors.initials: A
authors.lastname: Lee
authors.forename: Nathan
authors.initials: N
authors.lastname: Dascal
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D001665:Binding Sites; D002118:Calcium / Q000737:chemistry; D015220:Calcium Channels / Q000737:chemistry / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000378:metabolism*; D002147:Calmodulin / Q000737:chemistry; D005260:Female; D017353:Gene Deletion; D006801:Humans; D007700:Kinetics; D011485:Protein Binding; D020033:Protein Isoforms; D017434:Protein Structure, Tertiary; D014981:Xenopus
chemical_list: D015220:Calcium Channels; D020746:Calcium Channels, L-Type; D002135:Calcium-Binding Proteins; D002147:Calmodulin; C419385:L-type calcium channel alpha(1C); D020033:Protein Isoforms; C085577:Ca2+-binding protein-1; D002118:Calcium